Transplantation of hematopoietic stem cells has been widely used as an approved treatment of leukemia, lymphoma and certain autoimmune conditions for the past fifty years. Other adult stem cells have demonstrated safety and efficacy in pre-clinical research and clinical trials. Mesenchymal stem cell transplants have been most widely studied in animals, especially horses & dogs, and humans. Many of these studies have focused on skeletal-muscular effects.
There is significant support for safety and efficacy in osteoarthritis, including cartilage regeneration, pain and inflammation reduction as well as recovery of function using intra-articular MSC injections. There are fewer studies of neural stem cell and Satellite cell transplants, but these also suggest safety and efficacy in various conditions. There are minimal adverse effects of these stem cell transplants.
However, there are significant obstacles to routine clinical use of non-hematopoietic adult stem cell transplantation. First, therapeutic effect is dependent on cell concentration and exhibits characteristic dose-response relationships, necessitating expansion and characterization of MSCs prior to transplantation. While MSCs readily proliferate in vitro, this may result in cellular/genetic modifications and the cell culture conditions necessary for expansion of clinical grade MSCs have not yet been determined.
Autologous sources appear superior to allogeneic, but controlled expansion of autologous MSCs could be limited. Also, there are regulatory obstacles including the US FDA that considers expanded stem cells “altered” with associated regulatory burdens prior to approval. Thus, it is likely that MSC transplantation has a long and expensive pathway to attain routine clinical implementation.
There is an alternative approach to achieving stem cell therapy without transplantation. Adult stem cells exist in various tissues within the body including bone marrow, adipose tissue, within specific brain regions and also within blood and other tissues. While the hematopoietic stem cells within bone marrow differentiate rapidly producing ~200 billion red blood cells per day, other stem cells exist in a quiescence state and are activated by specific stimulation.
A cut to the skin, for example, results in the release of various substances that activate MSCs within bone marrow to migrate to the site of injury and begin the process of wound healing. Thus, quiescent stem cells residing within our tissues represent a vast reserve of potential therapeutic agents that can be awakened with the proper stimulus or “molecular switch”.
Recent research has identified some of the agents that activate endogenous stem cells that reside within the human body. Research published in May 2014 identified a blood protein called GDF11 (growth differentiation factor 11) that is mainly responsible for the reversal of aging found when old rats are transfused with young blood. GDF11 activates adult muscle stem (Satellite) cells. Researchers from the Stem Cell Institute at Harvard University showed that GDF11 reduced functional impairments and restored genomic integrity of Satellite cells yielding improved muscle strength & functional endurance.
Thus, while it is well-known that hematopoietic stem cells may be activated by growth factors and these have been used for over 20 years in the treatment of anemia and immune-suppression resulting from chemotherapy, it is likely that other types of adult stem cells can be activated by other specific factors that act as activators of Satellite cells, neural stem cells and MSCs. This knowledge may be translated to new avenues for stem cell therapy without the necessity of transplantation.
While stem cell transplants are clearly warranted for certain conditions including leukemia & lymphoma, there is growing evidence that activation of endogenous stem cells is an emerging approach to therapy. Latent stem cells require activation of specific biological signaling pathways including mobilization through chemokine signaling, proliferation/differentiation through Wnt pathway activation and epigenetic modulation of specific gene expression to become therapeutic.
Preclinical studies suggest efficacy of stem cell activation in traumatic brain injury (TBI), AD, Parkinson’s, ALS and spinal cord injury. Also, this approach may be appropriate therapy for inflammatory/autoimmune conditions including Crohn’s disease, MS, and several other conditions as well. Furthermore, recruitment of adult stem cells is associated with enhanced learning of perfect pitch and muscle function can be enhanced in mice by administration of PDF11, a stem cell activation agent. Thus, endogenous stem cell activation may not only be therapeutic but also used to enhance performance and possibly, longevity.
Stem cell activation awakens innate stem cell systems to optimize healing, cellular regeneration and functionality. This approach has numerous advantages over stem cell transplantation including innately autologous therapy without acute or long-term complications from introduction of allogeneic cellular materials.
The approach involves administration of an activating agent or agents and effects are controlled by dosage/pharmacokinetics of the stem cell mobilizing, epigenetic or proliferative agents thus avoiding transplantation issues including possible cellular modification during expansion, contamination, etc.
The pathway to regulatory approval is shorter and less costly since certain combinations of generic drugs may be effective and there are natural substances exhibiting apparent efficacy. Also, new drug targets are associated with this paradigm, such as specific combinations of proliferation and epigenetic agents.
Vitro Biopharma has been pursuing this approach for the past six months using patients treated within a clinical network. The primary approach is to resolve toxicity, infectivity and specific deficiencies thus restoring physiological conditions while monitoring clinical status. Optimum cellular functionality is viewed as a necessary condition to elicit therapeutic benefit from activation of endogenous stem cells.
We also use proteomic arrays to quantify various cytokines, growth factors and neurotrophins to develop disease profiles. We establish baseline results and are now testing agents known to activate stem cells to determine effects on the biomarker disease profile as well as clinical status. We are also developing additional biometric analysis of stem cell activation including MSC mobilization to peripheral blood, serum content of key stem cell biomarkers and tools for imaging of stem cell activation.
Vitro Biopharma is nearing commercialization of stem cell-based assays utilizing live cell imaging of cell migration, proliferation and reprogramming for drug discovery and support of clinical trials. We are also developing a clinical trial testing of stem cell activation for treatment of TBI and advanced molecular diagnostics while developing new stem cell activators.
Vitro Biopharma is committed to further development and testing of the activation of latent, internal stem cells since this approach is widely supported by pre-clinical research and obviates several problematic issues associated with the transplantation of adult stem cells.